During the 11th ICTHIC, Simon Mantha talked about the relationship between genetic cancer alteration and the risk of thrombosis. Here, we summarize the highlights of his speech.
Genes and thrombosis: why does it matter?
Studying the association between cancer genetic alteration and thrombosis is important to prevent and treat venous thromboembolism (VTE). In addition, it will lead us to a better capacity to predict and understand the molecular mechanisms behind cancer-associated thrombosis (CAT), which could potentially lead to new treatments and prophylactic modalities.
Cancer is a disease directly resulting from selection and evolution at the cellular level. Through this selection process, cancer cells can develop somatic alterations over a broad set of genes that can be grouped into two categories, oncogenes and tumor suppressor genes .
Coagulation activation is thought to confer a survival advantage to the tumor, and selection pressures on cancer cells tend to favor the emergence of a clone or polyclonal cellular ecosystem with the most procoagulant phenotype .
Since DNA is the substratum for the cellular selection events, cancer genetic alterations likely contain information about thrombosis risk. Knowing the relationship between cancer genetics and thrombosis could lead to better risk models, useful to stratify patients by risk of VTE. This will lead to targeting pharmacological prophylaxis more efficiently to individuals the most at risk.
Role of somatic genomic alteration in cancer-associated thrombosis
The mechanisms behind the pathogenesis of CAT are multifactorial and depend on the tumor and its DNA, the host, and the administered treatments. Some tumor-specific factors are known to promote VTE, such as tumor secretion of various procoagulant factors (e.g., tissue factor [TF]) with consequent activation of platelets, cytokines and leukocytes. In addition, secondary effects of tumor cells on the surrounding vasculature and tissue microenvironment occur .
The procoagulant effects of cancer somatic genetic alterations could be simplified as follows:
- a DNA alteration occurs in an oncogene or tumor suppressor gene followed by an aberrant mRNA transcription.
- The resulting oncoprotein produced can lead, in some cases, to changes in the extracellular secretion of cytokines and other proteins.
- These circulating mediators can lead to platelets and neutrophil activation.
- In addition, membrane-derived microparticles can be produced by activating the coagulation cascade, producing a procoagulant phenotype .
The most studied procoagulant effector in this simplified cascade is the TF, which activity can be mediated by alterations in several genes, such as ALK, ROS1, KRAS, IDH1/2, KEAP, STK11, EGFR, HER2 and more . The TF activates the extrinsic coagulation pathway and contributes to the genesis of CAT.
The ALK gene and its mutations are one of the most studied. The ALK gene is altered in about 1% of non-small-cell lung cancer (NSCLC) patients and is a therapeutic target. ALK alterations are associated with a doubled risk of CAT in patients with NSCLC [5,6].
ROS1 is another important gene in NSCLC and can enhance the risk of CAT by threefold in NSCLC patients. The cumulative incidence of total thromboembolism is estimated at 50% 3 years after diagnosis for ROS1 and 44% at 5 years for ALK [5,6].
KRAS alterations are more frequent in cancer associated with a higher risk of CAT (lung, pancreas and gastric cancer). KRAS alteration effects on CAT can vary, but it is sustained across cancer types .
Other mutations seem to have a positive influence on CAT risk. For example, mutations in IDH1 or IDH2 genes are generally found in primary brain tumors and are associated with a better prognosis.
A retrospective study showed that gliomas with wild-type IDH1/2 had a cumulative incidence of VTE of 26% compared with none with mutated IDH1/2. It seems that mutations in IDH1 lead to hypermethylation of a region of the TF gene promoter, leading to a decreased expression, which could explain the decreased risk of VTE in primary brain cancer patients with mutant IDH1 .
A recent study analyzed deep-coverage targeted DNA sequencing data of about 12,000 solid tumor samples using the Memorial Sloan–Kettering Integrated Mutation Profiling of Actionable Cancer Targets platform to identify somatic alterations associated with VTE .
In this study, the analysis supported the protective role of IDH1 for gliomas. Still, the protective effect did not reach statistical significance when looking at all tumor types and after adjustment for multiple comparisons. It seems that a differential action of IDH1-mutated status exists across cancer types, and no evidence was found of a protective effect from IDH1 mutations against VTE outside of gliomas. This suggests that the effects of IDH mutations on modulating VTE risk are mediated or influenced by as-yet-unknown cancer type-specific factors .
The study confirmed an increased risk of CAT for mutated STK11, CDKN2B, CTNNB1 and KEAP1 genes. However, the effect of KEAP1 was mitigated in multi-gene regression models, and its mutations are strongly correlated with STK11 defects, suggesting KEAP1 mutations might not be an independent predictor of CAT risk .
In addition, the mechanisms by which STK11 mutations are associated with an increased risk of VTE are unclear and might include increased neutrophil extracellular trap formation secondary to granulocyte colony-stimulating factor (G-CSF) production by the tumor .
Conflicting results are reported in the literature regarding EGFR mutations in lung cancer and VTE risk. The study did not show any association between CAT risk and EGFR. These results might be influenced by the different EGFR-directed therapies received by patients with lung cancer in different cohorts .
Unveil the association between genomic alteration and the risk of VTE is not a straightforward process because it involves a great number of predictors and variables. Genes can be modified in various ways, each one leading to a different result, and a series of other alterations contribute to influencing coagulation .
Additionally, CAT risk is not modulated by a single gene or pathway, but several genes participate in modulating the risk of VTE, and their role is influenced by the cancer type. For example, IDH1 seems to have a protective effect in gliomas but no effects in other cancer types. This is why data concerning genetic-related risk of VTE should be adjusted for cancer type .
In addition, cancer therapies could be a source of bias. For example, gene-targeted therapies could block procoagulant effects (e.g., EGFR-directed therapies). As a result, they can have a survival benefit, leading to an increased cumulative incidence of VTE due to a longer time at-risk .
Lastly, each cancer is a mosaic of different cells with peculiar genetic and epigenetic alterations that impact the phenotype. Therefore, the thrombotic effect of such heterogenous tumors doesn’t always mirror the dominant mutational event present in most of its cells .
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